A non-sustained release agent that reliably gives 6-12 hours of surgical-grade nerve block followed by up to approximately 48 h of lesser blockade and pain relief without additional treatment is desirable. The former period would be useful intra-operatively as well as in the immediately post-op period; the latter would provide decreasing analgesia and allow increasing use of the involved body part as healing progresses. Exparel™, the only prolonged duration local anesthetic on the market, provides unpredictable nerve blockade in humans that peaks at 24 h after injection and the anesthetic effect is inversely proportional to dose. Moreover it entails the use of a sustained release system and causes local tissue injury and inflammation.
Similar considerations relate to bupivacaine+dexamethasone microparticles, which could provide prolonged duration local anesthesia albeit with a sustained release system and with very severe tissue injury. The quaternary lidocaine derivative QX-314 could provide prolonged duration local anesthesia (approx. 24 h duration) but with very severe local tissue injury and systemic toxicity.
When amino-amide and amino-ester local anesthetics are given in overdose or via inadvertent intravascular injection, they generate cardiovascular toxicity that is notoriously refractory to resuscitation (Polaner et al. Ped Anes 2011; 21:737-742; Fisher, et al., Can. J. Anaesth., 1997; 44: 592-598; Butterworth, Reg. Anesth. Pain Med., 2010; 35:167-76). Bupivacaine cardiovascular toxicity is likely mediated by the cardiac sodium channel Nav1.5 which is relatively more resistant to binding and inactivation by site 1 sodium channel blockers (Clarkson, et al., Anesthesiology, 1985; 62:396-405).
The phycotoxins neosaxitoxin, saxitoxin and gonyaulatoxins are active compounds produced by harmful algae blooms of the genera Alexandrium sp., Piridinium sp., and Gimnodinium sp., (Lagos, N. Biol. Res., 31: 375-386 1998). In the last 15 years, it has been demonstrated that these phycotoxins can also be produced by fresh water cyanobacteria such as photosynthetic blue-green algae, besides being produced by marine dinoflagellates.
Only four genera of cyanobacteria able to produce paralyzing phycotoxins have been identified, and each produces a different mixture of phycotoxins both in amounts and in types of phycotoxins produced, i.e. they produce different profiles of paralyzing phycotoxins (Lagos, et al., 1999, TOXICON, 37: 1359-1373 (1999). Pereira, et al., TOXICON, 38: 1689-1702 (2000).
The chemical structure of these phycotoxins has a general structure (I) and its particular structure is defined by the substituents R1 to R5 according to the following table:
(I) CompoundR1R2R3R4R5SaxitoxinHHHCOONH2OHNeosaxitoxinOHHHCOONH2OHGonyaulatoxin 1OHHOSO−3COONH2OHGonyaulatoxin 2HHOSO−3COONH2OHGonyaulatoxin 3OHOSO−3HCOONH2OHGonyaulatoxin 4HOSO−3HCOONH2OHGonyaulatoxin 5HHHCOONHSO−3OH
These paralyzing phycotoxins act as a specific blocker of the voltage-dependent sodium channels present in excitable cells (Kao, C. Y., Pharm. Rev., 18: 997-1049 (1966)). Due to the inhibition of sodium channels, the transmission of a nervous impulse is blocked and the release of neurotransmitters is prevented at the level of the neuromotor junction, which prevents muscular contraction. Due to these physiological effects, these compounds are potentially useful in pharmacology when used as muscular activity inhibitors in pathologies associated with muscular hyperactivity, such as muscular spasms and focal dystonias, when applied locally in injectable form. Additionally, since a blockage of the nervous impulse at the transmission level is generated when these compounds are applied as a local infiltration, they are not only able to block the efferent neurotransmission pathways, but also block afferent pathways and cause an inhibition of the sensory pathways and generate an anesthetic effect when these compounds are locally injected. This is a surprising effect, since both effects are simultaneous, as described in U.S. Pat. No. 4,001,413.
As described in U.S. Pat. No. 6,326,020 by Kohane, et al., combinations of naturally occurring site 1 sodium channel blockers, such as tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, and neosaxitoxin, with other agents, have been developed to give long duration block with improved features, including safety and specificity. In one embodiment, duration of block is greatly prolonged by combining a toxin with a local anesthetic, vasoconstrictor, glucocorticoid, and/or adrenergic drugs, both alpha agonists (epinephrine, phenylephrine), and mixed central-peripheral alpha-2 agonists (clonidine), or other agents. Prolonged nerve block can be obtained using combinations of toxin with vanilloids. Dosage ranges based on studies with tetrodotoxin and saxitoxin were provided. However, it is now known that studies must be conducted with each toxin in order to predict the effective dosages, since dosages with one type of toxin are not predictive of efficacy with another type of toxin. As demonstrated in the following examples, it has also been discovered that one cannot extrapolate from rats or sheep to humans to determine safe and efficacious dosages with respect to these toxins.
Conventional local anesthetics are associated with local neurotoxicity in clinical doses and profound cardiovascular toxicity in overdose. While overall incidence is low, studies have also identified prolonged numbness and paresthesias as a complication of local and regional anesthesia with amide anesthetics. This has been associated with histological signs of chemical nerve injury (Myers, et al., Anesthesiology, 1986; 64:29-35; Kalichman, et al., J. Pharm. Exper. Therapeutics, 1989; 250(1):406-413). These risks for local neurotoxicity are likely to be further increased in the setting where prolonged pain relief is attempted via administration of conventional local anesthetics by controlled release delivery (Padera, et al., Anesthesiology, 2008; 108: 921-8; Kohane and Langer, Chem. Sci., 2010; 1: 441-446) or local perineural infusions, particularly when higher concentrations or doses are used for longer periods of time. In equipotent intrathecally injected doses, site 1 sodium channel blockers cause longer duration of anesthesia with less histologic evidence of neurotoxicity compared to bupivacaine (Sakura, et al., Anesth. Analg., 1995; 81:338-46). Overall, approaches to prolonged local anesthesia involving site 1 sodium channel blockers lower the risks of nerve injury compared to approaches involving prolonged or repeated administration of conventional amino-amides or amino-esters.
It is therefore an object of the present invention to provide specific combinations of neosaxitoxin with bupivacaine, optionally with epinephrine, to provide pain relief for up to two to three days following a single injection, which are both safe and efficacious in humans.
It is a further object of the present invention to provide formulations for providing safe and efficacious local anesthesia and analgesia in pediatric patients.
It is still another object of the present invention to provide formulations for treating indications requiring high, medium and low volumes of local anesthesia.
It is a further object of the present invention to provide formulations for treating indications requiring different rates of recovery from sensory or motor blockade due to local anesthesia.